Tailored approaches targeting crucial oncogenes and pathways have shown successful results in a number of cancer types and offer exciting perspective in neuro-oncology. IDH (Isocitrate dehydrogenase) wild-type (IDHwt) glioblastoma (GBM) (10%) present a unique and homogenous energetic metabolism which is specifically dependent on the oxidative phosphorylation (OXPHOS) rather than on the aerobic glycolysis. OXPHOS+ IDHwt GBMs overexpress mitochondrial markers and can be specifically inhibited by mitochondrial inhibitors in vitro and in vivo.
Metformin is an oral inhibitor of mitochondrial complex I and is a widely used drug in diabetic and non-diabetic patients, safe and well tolerated in association with radiotherapy and chemotherapy.
Basing on drastic effect, the investigators have observed in vivo (reduction of \>50% of tumor growth) and hypothesize that metformin could be specifically efficient to treat up-front patients affected by OXPHOS+ GBM, in association with the standard first-line treatment with radiotherapy and temozolomide (RT-TMZ).
The investigators set up a dedicated molecular analysis including RNA assay and expression of OXPHOS markers for formalin-fixed paraffin-embedded tumors (FFPE), which allows to detect OXPHOS+ GBM at diagnosis.
Here a phase II, open label, non-randomized multicenter trial including five French neurooncology centers (H. Foch-Suresnes, Pitié-Salpêtrière-Paris, Saint Louis-Paris, Lyon, Marseille) and one in Italy (Istituto Besta, Milan) is proposed.
Newly diagnosed IDH wild-type GBM patients with the OXPHOS+ signature will be eligible for inclusion in this trial. The investigators expect to screen 640 patients and to include 64 patients over a period of 24 months with 24 months of follow-up.
Provision of signed informed consent for selection and treatment phase obtained from the patient/legal representative prior to performing any protocol-related procedures,
Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits, and examinations including follow-up,
Newly-diagnosed histologically-confirmed supra-tentorial IDHwt glioblastoma (Grade 4 malignant glioma by World Health Organization, including gliosarcoma),
OXPHOS+ subtype by the central laboratory
Prior treatment for GBM (other than surgical resection) including Gliadel wafer,
Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years,
Any known metastatic extracranial or leptomeningeal disease,
IDH mutant,
Single group
Metformin
DrugMetformin 2000 to 3000mg/day daily will be started by 6 weeks after histological diagnosis and 7 days before the start of RT-TMZ and will continue until progression.
Radiation IMRT
Radiation2 Gy x 5 days for 6 weeks to be started 7 days after first administration of Metformin and by 7 weeks after histological diagnosis
Temozolomide
Drug75 mg/m² daily from first to last day of radiation (IMRT) and then 150 to 200 mg/m² x 5 days every 28 days cycle for 12 cycles
Assessement of Progression Free Survival (PFS) of patients with newly-diagnosed IDH wild-type OXPHOS + GBM (either with or without FGFR3-TACC3 gene fusion) treated with RT plus TMZ combined with metformin
Progression free survival (PFS) estimated by the RANO (Response Assesment in Neuro Oncology) criteria
Assessement of the Overall survival (OS) of treated patients
Overall survival (OS)
Assessement of the Overall Response rate (ORR)
Overall response rate (ORR) estimated by the RANO criteria
Assessement of the the safety of metformin in association with concomitant RT-TMZ
Type, frequency, and severity (grade III and IV toxicity) of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Assessement of the the tolerability of metformin in association with concomitant RT-TMZ
Dose interruptions, reductions and dose intensity.
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Hopital Foch
Lead sponsor
National Cancer Institute, France
Collaborator
